In the United States cancers of the colon and rectum are the third most common site of new cases and deaths. There were an estimated 148,300 new cases and 56,600 deaths from the disease in 2002. All too often, the cancer has metastasized by the time of diagnosis, and the most common site of distant metastasis is the liver. One promising strategy is immunotherapy that harnesses the antitumor effect of the patient's own immune system. Tumor cells combined with the paracrine release of granulocyte-macrophage colony stimulating factor (GM-CSF) are highly effective in generating potent T cell dependent systemic immunity capable of curing mice of very small burdens of pre-established tumors. The long-term objective of this proposal is to build an immunotherapy program against colorectal cancer based on GM-CSF tumor cell vaccines, and to translate novel therapeutic immunotherapeutic approaches from the laboratory to the clinics. The specific aims of this research proposal are: Specific Aim 1: To study the elements of the immune response of mice that eliminate established hepatic metastases after treatment with GM-CSF augmented tumor cell vaccines and to study mechanisms of focusing a systemically generated immune response into the liver. Specific Aim 2: A) To develop standard operating protocols to dissociate tumor cells from human colorectal cancer metastases to the liver so that they may be successfully isolated, irradiated, and stored for vaccine preparation. B) To produce a clinical lot of GM-CSF-secreting bystander cells. Specific Aim 3: To conduct a phase I clinical trial to study the safety and feasibility of a vaccine approach against colorectal cancer that combines autologous irradiated tumor cells isolated from hepatic metastases combined with a bystander cell line that secretes GM-CSF.